CN115028634B - Acetylenic pyrazino heterocycle FGFR inhibitor and preparation method and application thereof - Google Patents

Abstract

The application discloses an acetylenic pyrazino heterocyclic compound serving as an FGFR inhibitor, a preparation method and medical application thereof. Specifically, the application relates to a compound shown in a general formula I and pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the compound and or pharmaceutically acceptable salts thereof, and application of the compound or pharmaceutically acceptable salts in medicaments for treating or preventing FGFR kinase-related diseases, especially tumors, which are a class of acetylenic pyrazino heterocyclic compounds, and a preparation method of the pharmaceutical composition containing the compound or pharmaceutically acceptable salts thereof. Wherein each substituent of the general formula I is as defined in the specification.

Description

Acetylenic pyrazino heterocycle FGFR inhibitor and preparation method and application thereof

Technical field:

the present application relates to an acetylenic pyrazino-heterocyclic compound or a pharmaceutically acceptable salt thereof as an FGFR inhibitor; a pharmaceutical composition comprising said acetylenic pyrazino heterocyclic compound or a pharmaceutically acceptable salt thereof; a process for the preparation of said acetylenic pyrazino-heterocyclic compound or a pharmaceutically acceptable salt thereof; use of said acetylenic pyrazino-heterocyclic compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said acetylenic pyrazino-heterocyclic compound or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of FGFR-related disorders, in particular tumors.

The background technology is as follows:

fibroblast growth factors (fibroblast growth factors, FGFs) bind to their receptors (fibroblast growth factor receptors, FGFRs), activate their regulated downstream signaling pathways, and play an important role in biological processes such as mitogenesis (embryogenesis, growth development, etc.) and non-mitogenesis (neuromodulation, metabolic regulation, etc.). FGFRs are a typical class of Receptor Tyrosine Kinases (RTKs), whose family includes four subtypes FGFR1, FGFR2, FGFR3, and FGFR 4. They are composed of three parts, an extracellular region, a transmembrane region and an intracellular tyrosine kinase region. Wherein the extracellular region comprises 3 immunoglobulin-like structures (D1-D3), the D1 region has a self-inhibiting function, and the D2 and D3 regions and the linking region of D2-D3 are bound to the ligand. D3 of the iiib or iiic portions of FGFR1, FGFR2 and FGFR3 may undergo alternative splicing, thereby producing both isoforms of FGFRb or FGFRc, the difference in the D3 domain determining the ligand binding specificity of the FGFRs. FGFs require binding to FGFRs with the aid of heparan sulfate glycosaminoglycans (heparan sulphate glycosaminoglycan, HSGAG), causing FGFR dimerization, resulting in activation of multiple tyrosine residues of their intracellular tyrosine kinase domain by autophosphorylation. Activated FGFRs activate their substrates plcγ and signal adapter protein FRS2 by phosphorylation, and their substrates reactivate downstream MEK/MAPK, PI3K/AKT, PKC, STATS, etc. signaling pathways.

However, when FGFR is mutated or overexpressed, excessive activation of FGFR signaling pathways is caused, and normal cell canceration is further induced. Wherein, excessive activation of RAS-RAF-MAPK stimulates cell proliferation and differentiation; excessive activation of PI3K-AKT leads to inhibition of apoptosis; SATA is closely related to promoting tumor invasion and metastasis, enhancing tumor immune escape ability; the PLC gamma signal path is an important path for tumor cell metastasis regulation. According to a study published in Clinical CancerResearch in 2015, next Generation Sequencing (NGS) against 4853 types of solid tumors showed that FGFR aberrations (absences) were found and activated abnormally in approximately 7.1% of cancers, most of which were gene amplification (66%), followed by mutation (26%) and rearrangement (8%). FGFR aberration exists in almost all detected malignant tumors, and cancers with high incidence rate include urothelial cancer, cholangiocarcinoma, breast cancer, endometrial cancer, squamous carcinoma and the like; at the same time, abnormal activation of FGFR is also found in tumors such as lung cancer, liver cancer, breast cancer, etc.

There are some non-FGFR specific drugs on the market such as lenretini of Sunitinib, eisai and nintedanib of Boehringer Ingelheimr of pfizer. Whereas FDA approved FGFR inhibitors are only Balversa (Erdafitinib) and Pemazyre (pemigatinib). The FGFR-targeted inhibitor drug can inhibit abnormal activation of FGF/FGFR signal channels, has the potential of treating the diseases, and becomes one of the hot spots of drug research in recent years.

Although the development of FGFR inhibitors attracts to the layout of numerous companies at home and abroad, new compounds are still needed to be developed due to the prospect of their demonstration in the treatment of various malignant tumors. Through continuous efforts, the application designs irreversible inhibitors which have independent intellectual property and show excellent activity on FGFR-1-4 protein kinase.

Disclosure of Invention

The application provides a compound of an acetylenic heterocyclic derivative shown in a general formula I or a prodrug, a stable isotope derivative, a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, which can be used as an irreversible FGFR inhibitor,

wherein:

X ₁ ，X ₂ ，X ₃ ，X ₄ can be independently selected from N, CR ¹ ；

Ring B is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the benzene ring and the heteroaromatic ring are optionally substituted with one or more G ¹ Substituted;

R ¹ independently selected from H, cyano, halogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OR ² 、-NR ² R ³ 、-C(O)NR ² R ³ Wherein said alkyl, cycloalkyl OR heterocycloalkyl is optionally substituted with cyano, halogen, -OR ⁴ 、-NR ⁴ R ⁵ 、C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

u is independently selected from-C _0-4 Alkyl-, -CR ⁶ R ⁷ -、-C _1-2 Alkyl (R) ⁶ )(OH)-、-C(O)-、-CR ⁶ R ⁷ O-、-OCR ⁶ R ⁷ -、-SCR ⁶ R ⁷ -、-CR ⁶ R ⁷ S-、-NR ⁶ -、-NR ⁶ C(O)-、-C(O)NR ⁶ -、-NR ⁶ C(O)NR ⁷ -、-CF ₂ -、-O-、-S-、-S(O) _m -、-NR ⁶ S(O) ₂ -、-S(O) ₂ NR ⁶ -；

Y is absent or C is selected _3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spiroheterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocycloalkyl, spiroheterocyclyl, fused ring, fused heterocyclyl, spiroheterocyclyl, aryl or heteroaryl is optionally substituted with one or more G ² Substituted;

z is independently selected from cyano, -NR ⁸ CN、

Bond a is a double bond or a triple bond;

when a is a double bond, R ^a 、R ^b And R is ^c Each independently selected from H, cyano, halogen, C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl. Wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted with 1 or more G ³ Substituted;

R ^a and R is ^b Or R is ^b And R is ^c Optionally together with the carbon atoms to which they are attached form a 3-6 membered ring optionally containing heteroatoms;

when bond a is a triple bond, R ^a And R is ^c Absent, R ^b Independently selected from H, cyano, halogen, C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl groups substituted by one or more G ⁴ Substituted;

R ⁸ independently selected from H, C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted with 1 or more G ⁵ Substituted;

G ¹ 、G ² 、G ³ 、G ⁴ and G ⁵ Each independently selected from cyano, halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -OR ⁹ 、-OC(O)NR ⁹ R ¹⁰ 、-C(O)OR ⁹ 、-C(O)NR ⁹ R ¹⁰ 、-C(O)R ⁹ 、-NR ⁹ R ¹⁰ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ C(O)NR ¹⁰ R ¹¹ 、-S(O) _m R ⁹ or-NR ⁹ S(O) _m R ¹⁰ Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1 or more cyano, halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -OR ¹² 、-OC(O)NR ¹² R ¹³ 、-C(O)OR ¹² 、-C(O)NR ¹² R ¹³ 、-C(O)R ¹² 、-NR ¹² R ¹³ 、-NR ¹² C(O)R ¹³ 、-NR ¹² C(O)NR ¹³ R ¹⁴ 、-S(O) _m R ¹² or-NR ¹² S(O) _m R ¹³ Is substituted by a substituent of (2);

R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹¹ 、R ¹² 、R ¹³ and R is ¹⁴ Each independently selected from cyano, halogen, C _1-6 Alkyl, C _3-8 Cycloalkyl or 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl or phenyl; and m is 1 or 2.

Another embodiment of the present application relates to a compound of formula I or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, polymorph, solvate, isomer or mixture thereof.

In the following detailed description of the application, exemplary embodiments are set forth that utilize the principles of the present application. The features and advantages of the present application may be better understood by reference to the following summary.

The above-described aspects of the present application will be described in further detail below with reference to specific embodiments. It should not be understood that the scope of the above subject matter of the present application is only the following examples. All techniques based on the above are within the scope of the present application.

Certain chemical terms

Unless stated to the contrary, the following terms used in the specification and claims.

The expression "C" as used herein has the following meaning _x-y "means a range of carbon number wherein x and y are integers, e.g. C _3-8 Cycloalkyl means cycloalkyl having 3 to 8 carbon atoms, i.e. cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms. It is also to be understood that "C _3-8 "also includes any subrange therein, e.g. C _3-7 、C _3-6 、C _4-7 、C _4-6 、C _5-6 Etc.

"alkyl" refers to a straight or branched hydrocarbon group containing 1 to 20 carbon atoms, for example 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, and 2-ethylbutyl. The alkyl group may be substituted or unsubstituted.

"alkenyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond and typically 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1, 4-pentadienyl and 1, 4-butadienyl. The alkenyl group may be substituted or unsubstituted.

"alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond and typically from 2 to 20 carbon atoms, for example from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl. The alkynyl group may be substituted or unsubstituted.

"cycloalkyl" refers to a saturated cyclic hydrocarbyl substituent containing 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocyclic, typically containing 3 to 7 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may alternatively be bi-or tricyclic fused together, such as decalin, which cycloalkyl groups may be substituted or unsubstituted.

"heterocyclyl", "heterocycloalkyl", "heterocycle" refers to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise indicated, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, spiro or bridged ring systems, a nitrogen, carbon or sulfur atom on a heterocyclyl group may be optionally oxidized, a nitrogen atom may be optionally quaternized, and a heterocyclyl group may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule by a single bond through a carbon atom or heteroatom in the ring. The heterocyclic group containing a condensed ring may contain one or more aromatic or heteroaromatic rings as long as the atom attached to the remainder of the molecule is a non-aromatic ring. For the purposes of the present application, heterocyclyl is preferably a stable 4-11 membered monovalent non-aromatic mono-or bi-ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic mono-ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolyl, dihydrofuranyl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

"spiroheterocyclyl" refers to a5 to 20 membered, polycyclic heterocyclic group having one atom in common between the monocyclic rings (referred to as the spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but the electronic system in which none of the rings has complete conjugation is preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, with single spirocycloalkyl groups and double spirocycloalkyl groups being preferred. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro-cyclic group. Non-limiting examples of spiroheterocyclyl groups include:

"fused heterocyclyl" means a5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) _m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

"aryl" or "aryl" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.

"heteroaryl" or "heteroaryl" refers to a 5-16 membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. Unless otherwise indicated, heteroaryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems, so long as the point of attachment to the rest of the molecule is an aromatic ring atom, the nitrogen, carbon, and sulfur atoms of the heteroaromatic ring may be selectively oxidized, and the nitrogen atom may be selectively quaternized. For the purposes of the present application, heteroaryl groups are preferably stable 4-11 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-8 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxanyl, benzofuranonyl, benzofuranyl, benzonaphtofuranyl, benzopyronyl, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazole, furyl, imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quininyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, and the like. In the present application, the heteroaryl group is preferably a 5-8 membered heteroaryl group comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridyl, pyrimidinyl, thiazolyl. The heteroaryl group may be substituted or unsubstituted.

"halogen" means fluorine, chlorine, bromine or iodine.

"hydroxy" means-OH, "amino" means-NH ₂ "amido" means-NHCO-, -cyano "means-CN," nitro "means-NO ₂ "Isocyano" means-NC, "trifluoromethyl" means-CF ₃ 。

The term "heteroatom" or "hetero" as used herein alone or as part of other ingredients refers to an atom other than carbon and hydrogen, the heteroatom being independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but is not limited to these atoms, in embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different.

The term "fused" or "fused ring" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.

The term "spiro" or "spiro" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

"optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur, e.g., an "optionally alkyl-substituted heterocyclic group" means that alkyl may but need not be present, and that the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.

"substituted" means that one or more atoms, preferably 5, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. It goes without saying that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort, the substituents being in their possible chemical positions. For example, a carbon atom having a free amine or hydroxyl group bonded to an unsaturated (e.g., olefinic) bond may be unstable. The substituents include, but are not limited to, hydroxy, amino, halogen, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl groups, and the like.

"pharmaceutical composition" refers to a composition comprising one or more of the compounds described herein or a pharmaceutically acceptable salt or prodrug thereof, and other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and further exert biological activity.

"isomer" refers to a compound having the same molecular formula but differing in the nature or sequence of their atoms bonded or the spatial arrangement of their atoms, and is referred to as an "isomer" and an isomer differing in the spatial arrangement of its atoms is referred to as a "stereoisomer". Stereoisomers include optical isomers, geometric isomers and conformational isomers. The compounds of the present application may exist in the form of optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are in the "R" or "S" configuration. Optical isomers include enantiomers and diastereomers, and methods for preparing and separating optical isomers are known in the art.

The compounds of the application may also exist as geometric isomers. The present application contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configuration, and substituents around cycloalkyl or heterocycle are designated as cis or trans configuration.

The compounds of the application may also exhibit tautomerism, such as keto-enol tautomerism.

It is to be understood that the present application includes any tautomeric or stereoisomeric form and mixtures thereof, and is not limited to any one tautomeric or stereoisomeric form used in the naming or chemical formulae of the compounds.

"isotopes" are all isotopes of atoms that are present in compounds of the application. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into compounds of the application are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, each such as, but not limited to ² H、 ³ H、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and F ³⁶ Cl. Isotopically-labeled compounds of the present application can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labeled reagent in place of a non-isotopically-labeled reagent. Such compounds have a variety of potential uses, for example as standards and reagents in assaying biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.

By "prodrug" is meant that the compounds of the application may be administered in the form of a prodrug. Prodrugs refer to derivatives of the biologically active compounds of the present application which are converted under physiological conditions in vivo, e.g., by oxidation, reduction, hydrolysis, etc. (each of which is performed with or without the aid of an enzyme). Examples of prodrugs are the following compounds: wherein the amine groups in the compounds of the application are acylated, alkylated or phosphorylated, such as eicosanoylamino, propylamino, pivaloyloxymethylamino, or wherein the hydroxyl groups are acylated, alkylated, phosphorylated or converted to borates, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, propylaminooxy, or wherein the carboxyl groups are esterified or amidated, or wherein the sulfhydryl groups form disulfide bridges with carrier molecules, such as peptides, that selectively deliver the drug to the target and/or cytosol of the cell, these compounds may be prepared from the compounds of the application according to well known methods.

"pharmaceutically acceptable salts" or "pharmaceutically acceptable" refer to those prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the application contain one or more acidic or basic groups, the application also encompasses their corresponding pharmaceutically acceptable salts. Thus, the compounds according to the application containing acidic groups may be present in salt form and may be used according to the application, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium salts or salts with amines or organic amines, such as primary, secondary, tertiary, cyclic amines, etc., for example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, and caffeine, and particularly preferred organic bases are salts of isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The compounds of the application containing basic groups may be present in salt form and may be used according to the application in the form of their addition to inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of the application contain both acidic and basic groups in the molecule, the application includes, in addition to the salt forms mentioned, also internal salts or betaines. The individual salts are obtained by conventional methods known to the person skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.

Thus, in the present application, when referring to "a compound", "a compound of the application" or "a compound of the application" all such compound forms, e.g. prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers, meso, racemates, enantiomers, diastereomers and mixtures thereof are included.

Herein, the term "tumor" includes benign tumors and malignant tumors (e.g., cancers).

As used herein, the term "cancer" includes various malignant tumors that Bruton's tyrosine kinase participates in, including but not limited to, non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyodur, cellular cancer, multiple myeloma, breast cancer ovarian cancer, endometrial cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer and liver cancer (e.g., hepatocellular cancer), more particularly liver cancer, gastric cancer and bladder cancer.

The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.

The term "polymorph" or "polymorphic form" as used herein means that a compound of the present application has a plurality of crystalline forms, some compounds of the present application may have more than one crystalline form, and the present application encompasses all polymorphic forms or mixtures thereof.

Intermediate compounds of the application and polymorphs thereof are also within the scope of the present application.

Crystallization often yields solvates of the compounds of the present application, and the term "solvate" as used herein refers to a complex composed of one or more molecules of the compounds of the present application and one or more molecules of a solvent.

The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent is also possible. Thus, the compounds of the present application may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the application may be true solvates, but in other cases the compounds of the application may simply accidentally retain water or a mixture of water with some other solvent, the compounds of the application may be reacted in one solvent or precipitated or crystallized in one solvent. Solvates of the compounds of the present application are also included within the scope of the present application.

The term "acceptable" in relation to a formulation, composition or ingredient as used herein means that there is no sustained detrimental effect on the overall health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.

"pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizer isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administration for use in humans and domestic animals.

The terms "subject," "patient," "subject," or "individual" as used herein refer to an individual having a disease, disorder, or condition, and the like, including mammals and non-mammals, examples of which include, but are not limited to, any member of the class mammalia: human, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.

The term "treatment" as used herein refers to the treatment of a disease condition associated with a mammal, particularly a human, including

(i) Preventing the occurrence of a disease or condition in a mammal, particularly a mammal that has been previously exposed to a disease or condition but has not been diagnosed with the disease or condition;

(ii) Inhibiting the disease or disorder, i.e., controlling its progression;

(iii) Alleviating the disease or condition, i.e., slowing the regression of the disease or condition;

(iv) Relieving symptoms caused by diseases or symptoms.

The terms "disease" and "disorder" as used herein may be used interchangeably or differently and, because some specific diseases or disorders have not yet been known to cause a disease (and therefore the cause of the disease is not yet known), they cannot be considered as a disease but rather can be considered as an unwanted condition or syndrome, more or less specific symptoms of which have been confirmed by clinical researchers.

The terms "administering," "administering," and the like as used herein refer to methods that enable delivery of a compound or composition to a desired site for biological action. Including, but not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

Synthesis method

The application also provides a method for preparing the compound. The preparation of the compounds of formula I of the present application may be accomplished by the following exemplary methods and examples, which should not be construed as limiting the scope of the application in any way. The compounds of the present application may also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of methods known in the art and methods described herein. The product obtained in each step is obtained using separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis can be synthesized conventionally according to the literature (reaxys) or purchased.

The acetylenic pyrazino heterocyclic compounds of the general formula I can be synthesized according to the following route: 1. the initial material A1 and the precursor H-U-Y-Boc generate aromatic nucleophilic substitution reaction under the action of alkali to generate A2; 2. a2 is brominated to generate A3 under the action of NBS; 3. a3 is coupled through sonogashira to obtain A4; 3. removing protection of amine groups in A4 to obtain A5; 4. the amine group in A5 is derivatized with a chemical reagent (e.g., allylic chloride, etc.) containing a functional group that is reactive with a cysteine residue within the kinase ligand binding domain to provide a compound of formula I.

Unless otherwise indicated, temperatures are degrees celsius. Reagents were purchased from commercial suppliers such as chemlocks Inc, astatech Inc or michelin and these reagents were used directly without further purification unless otherwise indicated.

Unless otherwise indicated, the following reactions were carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or gas, or using dry tubes; glassware drying and/or heat drying.

Column chromatography purification uses 200-300 mesh silica gel from the Qingdao marine chemical plant unless otherwise indicated; preparation of thin layer chromatography A thin layer chromatography silica gel prefabricated plate (HSGF 254) manufactured by Kagaku chemical industry research institute of tobacco, inc.; MS was determined using a Therno LCD Fleet type (ESI) liquid chromatograph-mass spectrometer.

Nuclear magnetic data [ ] ¹ H NMR) using Bruker Avance-400MHz or Varian Oxford-400Hz nuclear magnetic instruments with CDCl as solvent for the nuclear magnetic data ₃ 、CD ₃ OD、D ₂ O、DMSO-d ₆ Etc., based on tetramethylsilane (0.000 ppm) or on residual solvent (CDCl) _3: 7.26ppm；CD ₃ OD:3.31ppm；D ₂ O:4.79ppm；DMSO-d ₆ 2.50 ppm) when peak shape diversity is indicated, the following abbreviations represent the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet), dt (doublet). If the coupling constant is given, it is in Hertz (Hz).

Example 1: preparation of 2- (1-acrylamido-3-pyrrolidinyl) -7- (3, 5-dimethoxyphenylethynyl) -5H-pyrrolo [2,3-b ] pyrazine (Compound 1)

Step 1: synthesis of Compound 1b

Adding into a reaction bottleCompound 1a (1.98 g,10.0 mmol), 3-t-butoxycarbonylaminopyrrolidine (2.24 g,12.0 mmol), potassium carbonate (2.07 g,15.0 mmol) and N, N-dimethylformamide 40ml. The reaction was allowed to react overnight at 80℃with stirring. Cooled to room temperature, the reaction was diluted with ethyl acetate and water, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to give compound 1b (2.61 g, yield 86%) as a yellow solid. LC/MS (ESI) m/z=204.1 [ M+H ]] ⁺ .

Step 2: synthesis of Compound 1c

Compound 1b (1.82 g,6.0 mmol), N, N-dimethylformamide (20 ml) and NBS (1.60 g,9.0 mmol) were added in portions and reacted overnight at 50℃with stirring. Cooled to room temperature, the reaction mixture was poured into 100ml of water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to give compound 1c (1.42 g, yield 62%) as a yellow solid. LC/MS (ESI) m/z=282.0 [ M+H ]] ⁺ .

Step 3: synthesis of Compound 1d

In a reaction flask was charged compound 1c (1.15 g,3.0 mmol), 3, 5-dimethoxyphenylacetylene (0.58 g,3.6 mmol), ditriphenylphospholorium dichloride (211 mg,0.3 mmol), cuprous iodide (57 mg,0.3 mmol), triethylamine (1.01 g,10.0 mmol) and N, N-dimethylformamide (6 ml). The reaction was carried out overnight at 80℃with stirring by 3 nitrogen substitutions. Cooled to room temperature, the reaction was diluted with ethyl acetate and water, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to give compound 1d (1.10 g, yield 79%) as a yellow solid. LC/MS (ESI) m/z=364.2 [ M+H ]] ⁺ .

Step 4: synthesis of Compound 1e

To the reaction flask was added intermediate 1d (0.93 g,2.0 mmol), 4ml ethyl acetate, 4N HCl in 1, 4-dioxane solution, 4ml. The mixture was stirred at room temperature for 1 hour, the reaction mixture was neutralized with 1N sodium hydroxide solution, and extracted with ethyl acetate. The obtained organic phase was washed with saturated sodium bicarbonate and saturated brineDry over anhydrous sodium sulfate and evaporate the organic phase under reduced pressure. Compound 1e (0.68 g, 93% yield) was obtained as a yellow oil, which was used directly in the next step. LC/MS (ESI) m/z=364.2 [ M+H ]] ⁺ .

Step 5: synthesis of Compound 1

To the reaction flask was added compound 1e (803 mg,1.0 mmol), triethylamine (152 mg,1.5 mmol), 4ml dichloromethane, and after cooling in an ice-water bath, a solution of acryloyl chloride (136 mg,1.5 mmol) in 0.5ml dichloromethane was slowly added dropwise. Stirring was continued for 3 hours after the addition was completed. The reaction mixture was quenched with methanol and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 1 (225 mg, yield 54%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.52(s,1H),8.37(s,1H),7.98(s,1H),6.72(d,2H),6.52-6.45(m,2H),6.17(dd,1H),5.53(dd,1H),4.25(s,1H),3.80(s,6H),3.72-3.30(m,4H),3.02-2.83(m,1H),2.04-1.71(m,2H)；LC/MS(ESI):m/z＝418.2[M+H] ⁺ .

Example 2: preparation of (R) -2- (1-acrylamido-3-pyrrolidinyl) -7- (3, 5-dimethoxyphenylethynyl) -5H-pyrrolo [2,3-b ] pyrazine (Compound 2)

Referring to example 1, step one intermediate was replaced with (R) -3-t-butoxycarbonylaminopyrrolidine. The nuclear magnetic resonance and mass spectrum data were the same as in example 1.

Example 3: preparation of (S) -2- (1-acrylamido-3-pyrrolidinyl) -7- (3, 5-dimethoxyphenylethynyl) -5H-pyrrolo [2,3-b ] pyrazine (Compound 3)

Referring to example 1, step one intermediate was replaced with (S) -3-t-butoxycarbonylaminopyrrolidine. The nuclear magnetic resonance and mass spectrum data were the same as in example 1.

Example 4: preparation of 2- (1-acrylamido-3-azetidinyl) -7- (3, 5-dimethoxyphenylethynyl) -5H-pyrrolo [2,3-b ] pyrazine (Compound 4)

Using a method similar to example 1 (intermediate changed to 3-t-butoxycarbonylaminoazetidine), compound 3 (138 mg, yield 32%, this was the final step yield, the same as below) was obtained as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.55(s,1H),8.38(s,1H),7.94(s,1H),6.72(d,2H),6.50(t,1H),6.38(dd,1H),6.12(dd,1H),5.47(dd,1H),4.23(s,1H),4.03-3.91(m,3H),3.80(s,6H),3.27-2.83(m,2H)；LC/MS(ESI):m/z＝404.2[M+H] ⁺ .

Example 5: preparation of (R) -2- (but-2-ynylamido-3-pyrrolidine) -7- (3, 5-dimethoxyphenylethynyl) -5H-pyrrolo [2,3-b ] pyrazine (Compound 5)

Intermediate (R) -2- (3-aminopyrrolidine) -7- (3, 5-dimethoxyphenylethynyl) -5H-pyrrole [2,3-b ] in example 2]Pyrazine and 2-butynoyl chloride reacted to give compound 5 (159 mg, 38% yield) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.55(s,1H),8.35(s,1H),8.01(s,1H),6.73(d,2H),6.50(t,1H),4.39(s,1H),3.91-3.58(m,10H),3.24-3.16(m,1H),2.32-1.74(m,5H)；LC/MS(ESI):m/z＝430.2[M+H] ⁺ .

Example 6: preparation of (S) -2- (but-2-ynylamido-3-pyrrolidine) -7- (3, 5-dimethoxyphenylethynyl) -5H-pyrrolo [2,3-b ] pyrazine (Compound 6)

Using the intermediate (S) -2- (3-aminopyrrolidine) -7- (3, 5-dimethoxyphenylethynyl) -5H-pyrrolo [2,3-b ] pyrazine and 2-butynoyl chloride in example 3, compound 6 (142 mg, 34% yield) was obtained as a yellow solid. The nuclear magnetic resonance and mass spectrum data were the same as in example 5.

Example 7: preparation of 2- (1-acrylamido-3-piperidinyl) -7- (3, 5-dimethoxyphenylethynyl) -5H-pyrrolo [2,3-b ] pyrazine (Compound 7)

Using a method similar to example 1 (intermediate was changed to 3-tert-butoxycarbonylaminopiperidine), compound 3 (196 mg, yield 47%) was obtained as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.52(s,1H),8.35(s,1H),7.98(s,1H),6.72(d,2H),6.52-6.45(m,2H),6.17(dd,1H),5.52(dd,1H),4.29(s,1H),3.93-3.40(m,10H),3.15-3.04(m,1H),2.23-1.67(m,4H)；LC/MS(ESI):m/z＝432.2[M+H] ⁺ .

Example 8: preparation of 2- (1-acrylamido-4-piperidinyl) -7- (3, 5-dimethoxyphenylethynyl) -5H-pyrrolo [2,3-b ] pyrazine (Compound 8)

Using a method similar to example 1 (intermediate changed to 4-tert-butoxycarbonylaminopiperidine), compound 8 (212 mg, 51% yield) was obtained as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.54(s,1H),8.37(s,1H),7.99(s,1H),6.72(d,2H),6.52-6.45(m,2H),6.21(dd,1H),5.50(dd,1H),4.33(s,1H),3.80(s,6H),3.69-3.31(m,4H),3.01-2.85(m,1H),2.34-1.73(m,4H)；LC/MS(ESI):m/z＝432.2[M+H] ⁺ .

Example 9: preparation of 2- (2-propenoyl-2-azaspiro [3,3] heptane-6-amino) -7- (3, 5-dimethoxyphenylethynyl) -5H-pyrrolo [2,3-b ] pyrazine (Compound 9)

In a similar manner to example 1 (intermediate was changed to 6-amino-2-azaspiro [3.3 ]]Heptane-2-carboxylic acid tert-butyl ester) gave compound 9 (97 mg, yield 23%) asYellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.57(s,1H),8.37(s,1H),8.04(s,1H),6.72(d,2H),6.50(t,1H),6.11(dd,1H),5.84(s,1H),5.36(dd,1H),3.80(s,6H),3.67-3.31(m,4H),3.11-3.02(m,1H),2.21-1.83(m,4H)；LC/MS(ESI):m/z＝432.2[M+H] ⁺ .

Example 10: inhibition assay for in vitro Activity of kinases FGFR1, FGFR2, FGFR3 and FGFR4

FGFR1, FGFR2, FGFR3 and FGFR4 protein kinase activity was determined using Caliper mobility shift detection technology (Caliper mobility shift assay). Compounds were dissolved in DMSO and diluted in kinase buffer, and 5. Mu.L of 5-fold final concentration of compound (10% DMS 0) was added to 384-well plates. After adding 10. Mu.L of 2.5-fold enzyme (FGFR 1, FGFR2, FGFR3 and FGFR4 respectively) solution, incubation was performed for 10 minutes at room temperature, and then 10. Mu.L of 2.5-fold substrate (FAM-labeledpeptide andATP) solution was added. After incubation at 28℃for 30-60 min, the reaction was stopped by adding 25. Mu.L of stop solution (pH 7.5100mM HEPES,0.015%Brij-35,0.2%Coating Reagent#3,50mM EDTA). Conversion data was read on Caliper EZ Reader II (Caliper Life Sciences). Conversion was converted to inhibition data (% inhibition= (max-sample conversion)/(max-min) ×100). Where max refers to the conversion of the DMSO control and min refers to the conversion of the no enzyme activity control. Curves were plotted with compound concentration and inhibition as the abscissa and ordinate, fitted using XLFit exceladd-in version4.3.1 software and IC calculated ₅₀ . The assay results are shown in the following table, which shows the activity data of compounds 1-9 for kinases FGFR1, FGFR2, FGFR3 and FGFR 4. Active utilization IC ₅₀ Characterization, wherein "A" represents IC ₅₀ Less than or equal to 10nM; "B" means 10<IC ₅₀ Less than or equal to 100nM; "C" means 100<IC ₅₀ Less than or equal to 500nM; "D" means 500<IC ₅₀ ≤2000nM。

Claims (4)

1. An acetylenic pyrazino-heterocyclic FGFR inhibitor, characterized by being selected from any one of the following compounds:

or a pharmaceutically acceptable salt thereof, and mixtures thereof.

2. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of FGFR mediated diseases.

4. The use of claim 3, wherein the FGFR-mediated disease is one or more of non-small cell lung cancer, esophageal cancer, melanoma, gastric cancer, multiple myeloma, liver cancer, cholangiocarcinoma, prostate cancer, skin cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, breast cancer, colon cancer, glioma, and rhabdomyosarcoma.